Second Line Therapy in Multiple Myeloma: A SEER Medicare Analysis.

INTRODUCTION: The therapeutic landscape in relapsed/refractory multiple myeloma (RRMM) has changed rapidly, with twenty-two drug approvals since 2012. We characterized population-level trends in RRMM therapy selection, survival and cost outcomes associated with RRMM treatment over time. MATERIALS AND METHODS: Our cohort included adults diagnosed with multiple myeloma (MM) in the SEER-Medicare database from 2007-2017 who received at least one antimyeloma agent. MM-directed therapies and lines of therapy were identified. Changes in 2LT regimens over time were described. Trends in overall survival from 2LT initiation over time were analyzed using a Cox proportional hazards model adjusting for factors associated with survival in MM. Trends in mean inflation-adjusted cost per 12 months of 2LT were analyzed using JoinPoint analysis. RESULTS: A total of 9,822 patients met eligibility criteria, of whom 5,866 (59.7%) received 2LT. By 2018, 46% of 2LT regimens contained at least one agent approved in 2012 or later. Year of 2LT initiation was associated with improved overall survival (HR 0.78 per 5 years, 95% CI 0.74-0.84) after adjustment. Costs associated with 2LT increased over the study period, and the rate of cost increase increased significantly after 2012 (0.89%/year vs. 9.9%/year, P < .001), with higher total costs for regimens containing newer novel agents (mean $224,193 vs. $189,381, P < .001) CONCLUSION: Overall survival after initiation of 2LT has improved, however this has been accompanied by significant increases in costs of RRMM treatment, particularly for patients receiving newer novel agents. These findings provide useful context for existing and future drug approvals in RRMM.

Geriatric assessment-guided interventions for older adults with multiple myeloma: A feasibility and acceptability study.

INTRODUCTION: Geriatric assessment (GA)-guided supportive care programs have been successful in improving treatment outcomes for older adults with solid-organ cancers. This study aimed to evaluate the feasibility of a GA-guided supportive care program among older adults treated for multiple myeloma (MM). MATERIALS AND METHODS: The study utilized an existing registry of adults with plasma cell disorders at the University of North Carolina. Patients with MM, aged 60 or older, and having a GA-identified deficit in one or more problem area were offered referrals to supportive care resources during routine visits. Problem areas included physical function deficits, polypharmacy, and anxiety or depression. Patients with physical function deficits were offered referral to physical therapy (PT), those with polypharmacy to an Oncology Clinical Pharmacist Practitioner (CPP), and those with mental health symptoms to the Comprehensive Cancer Support Program (CCSP). RESULTS: Of the 58 individuals identified as having at least one deficit on the GA, PT was the most commonly identified relevant resource (79%), followed by CPP visits (57%). Among individuals that were offered referral(s) to at least one new supportive care resource, the acceptance rate was 50%. Referral acceptance rates were highest among those recommended for a CPP visit (55% of those approached) and lowest for CCSP (0%). DISCUSSION: The study examined the feasibility and acceptability of a referral program for supportive care resources among older adults with MM who have deficits on GA. The most commonly identified deficit was physical functioning, followed by polypharmacy and mental health. The study found that physical interventions and referrals to CPPs were the most accepted interventions. However, the low proportion of patients who accepted physical therapy referrals indicates the need for tailored and more personalized approaches. Further research is needed to explore the feasibility and impact of supportive care referral programs for older adults with MM.

Cross-Sectional Analysis of Clinical Trial Availability and North Carolina Neighborhood Social Vulnerability.

PURPOSE: Residents of communities facing social vulnerability (eg, poverty) have limited access to clinical trials, leaving them susceptible to experiencing poor health outcomes. We examined the association between North Carolina county-level social vulnerability and available multiple myeloma (MM) trials. METHODS: Using a novel data linkage between ClinicalTrials.gov, the 2019 American Community Survey, and the Centers for Disease Control and Prevention's Social Vulnerability Index, we investigated at the county level (1) availability of MM trial sites and (2) the relationship between Social Vulnerability Index and MM trial site availability using logistic regression. RESULTS: Between 2002 and 2021, 229 trials were registered across 462 nonunique trial sites in 34 counties. Nearly 50% of trial sites were in academic medical centers, 80% (n = 372) of all trials were industry-sponsored, 60% (n = 274) were early-phase, and 50% (n = 232) were for patients with relapsed or refractory MM. Counties with low as opposed to high poverty rates had six times greater odds of having ≥ 1 MM trial sites (odds ratio [OR], 5.60; 95% CI, 1.85 to 19.64; P = .004). Counties with the lowest percentage of Black Indigenous Persons of Color and non-native English speakers had 77% lower odds (OR, 0.23; 95% CI, 0.07 to 0.69; P = .011) of having ≥ 1 trial sites. The effect remained significant after accounting for the presence of five academic medical centers (n = 95; OR, 0.18; 95% CI, 0.05 to 0.6; P = .008) and adjustment for metropolitan, suburban, or rural status (OR, 0.25; 95% CI, 0.07 to 0.81; P = .025). CONCLUSION: Counties with the lowest poverty rates had more MM trial sites, whereas those with the lowest percentage of Black Indigenous Persons of Color populations had fewer MM trial sites. Multilevel efforts are needed to improve the availability and access to trials for socially vulnerable populations.

Localized light chain amyloidosis: A self-limited plasmacytic B-cell lymphoproliferative disorder.

Immunoglobulin light chain amyloidosis can be either systemic or localized. Although these conditions share a similar name, they are strikingly different. Localized light chain amyloidosis has been challenging to characterize due to its lower incidence and highly heterogeneous clinical presentation. Here, we review the emerging literature, emphasizing recent reports on large cohorts of patients with localized amyloidosis, and provide insights into this condition's pathology and natural history. We find that patients with localized amyloidosis have an excellent prognosis with overall survival similar to that of the general population. Furthermore, the risk of progression to systemic disease is low and likely represents initial mischaracterization as localized disease. Therefore, we argue for the incorporation of more sensitive techniques to rule out systemic disease at diagnosis. Despite increasing mechanistic understanding of this condition, much remains to be discovered regarding the cellular clonal evolution and the molecular processes that give rise to localized amyloid formation. While localized surgical resection of symptomatic disease is typically the treatment of choice, the presentation of this disease across the spectrum of plasmacytic B-cell lymphoproliferative disorders, and the frequent lack of an identifiable neoplastic clone, can make therapy selection a challenge in the uncommon situation that systemic chemotherapy is required.

Longitudinal Analysis of Patient-Reported Cognitive Function in Multiple Myeloma.

BACKGROUND: Cancer-related cognitive impairment (CRCI) has been largely unstudied in patients with multiple myeloma (MM). This study describes patient-reported cognition over time and patient factors associated with adverse cognitive outcomes in MM. METHODS: Participants enrolled in a registry in which they completed a geriatric assessment at study entry, and 3 & 6 months after entry. Cognitive function was assessed using the EORTC QLQ-C30 Cognitive Function subscale, with CRCI defined as scores < 75. Generalized estimating equation (GEE) models were used to fit longitudinal models to investigate differences by group and differences in changes over time by group, with adjustment for time since diagnosis. RESULTS: One hundred and four adults with MM had mean age of 67 years and 30% identified as Black. Patient-reported CRCI was present in 18% of participants at enrollment, 21% at 3 months, and 30% at 6 months. Worse cognitive function was reported in those with impairments in physical function (P = .002), IADLs (P = .02), and performance status (P = .04), as well as in those who were prefrail/frail (P = .02) and depressed (P = .049). Greater cognitive decline over time was observed in patients without CRCI at enrollment (P < .0001) and those with lower levels of education (P = .04). CONCLUSION: This is one of the first studies to describe longitudinal changes in patient-reported cognition in patients with MM. Several potentially intervenable factors, including physical function impairment and depression, were associated with worse cognition at study entry, but only baseline CRCI status and education level were predictive of future decline.

Physical Function, Psychosocial Status, and Symptom Burden Among Adults with Plasma Cell Disorders and Associations with Quality of Life.

BACKGROUND: The plasma cell disorders (PCDs), multiple myeloma (MM), and light-chain amyloidosis (AL) are disproportionately diseases of older adults, whose care may be complicated by frailty associated with advancing age. We sought to evaluate the prevalence of functional deficits and symptoms in a cohort of persons with PCDs and associations of demographic, disease-related, functional, and psychosocial measures with quality of life (QoL). PATIENTS AND METHODS: Adults with PCDs were recruited into an observational registry in 2018-2020. Patients completed a functional assessment and European Organization for Research and Treatment of Cancer QoL questionnaire (QLQ-C30). Associations of covariates of interest with QoL were evaluated via univariate linear regression. RESULTS: Among 121 adults, the mean age was 68.6. Diagnoses were 74% MM, 14% AL, 7% both MM and AL, and 5% other PCDs. The median time from diagnosis was 34.9 months. Median lines of therapy were 2, with 11% having received ≥4th-line therapy.Patients with functional deficits had lower mean QoL scores: dependence in IADLs (66.3 vs. 79.9, P = .001) and recent falls (56.7 vs. 76.8, P = .001). Patients ≤6 months from diagnosis had lower QoL (66.7) than those ≥2 years from diagnosis (77.3, P = .03). However, patients on later lines of therapy (≥4th-line) had lower QoL (62.2) than those on 1st-line treatment (76.0, P = .04). CONCLUSIONS: Patients with physical impairments and more advanced PCDs had lower QoL than those without deficits or earlier in their disease course. Early identification of physical impairments may facilitate interventions that mitigate these deficits and thereby improve QoL for patients with PCDs.

Prevalence and clinical correlates of cognitive impairment in adults with plasma cell disorders.

INTRODUCTION: Older adults with plasma cell disorders (PCDs) experience cognitive dysfunction that may be attributable to the disease and associated therapies. Yet, this has seldom been reported in the literature. Our objectives were to describe cognitive function (objective and patient-reported) in adults with PCDs and to explore clinical correlates of cognitive impairment. MATERIALS AND METHODS: Participants completed a geriatric assessment between March 2018 and February 2020. Cognitive function was evaluated using two objective measures - Montreal Cognitive Assessment (MoCA, cutpoint <26) and Blessed Orientation Memory Concentration Test (BOMC, cutpoint >4) - and two patient-reported outcome (PRO) measures - Patient-Reported Outcomes Measurement Information System Cognitive Function (PROMIS-CF, cutpoint <45) and European Organization for Research and Treatment of Cancer Cognitive Functioning subscale (EORTC-CF, cutpoint <75). Spearman correlations examined relationships among these measures and log binomial regression was used to examine characteristics associated with cognitive impairment, as defined by the MoCA and PROMIS-CF measures. RESULTS: Among 86 participants with a mean age of 69 (range: 46-91), the prevalence of cognitive dysfunction was between 20% (BOMC) and 63% (MoCA). There was moderate correlation among objective measures (r = 0.51, p < 0.0001), moderate to high correlation among PRO measures (r = 0.69, p < 0.0001), but no correlation between objective and PRO measures. Factors associated with objective impairment included ≤ high school education (RR 1.46, p = 0.009), living alone (RR 1.42, p = 0.02), relapsed/refractory disease (RR 1.39, p = 0.04), empirically de-intensified induction therapy (RR 1.62, p = 0.008), frailty (RR 1.49, p = 0.04), and peripheral vascular disease (RR 1.54, p = 0.002). Factors associated with PRO impairment included social isolation (RR 3.43, p = 0.003), depression (RR 3.30, p = 0.004) and anxiety (RR 4.43, p = 0.0002), frailty (RR 3.60, p = 0.02), falls in the previous 6 months (RR 2.53, p = 0.02), and deficits in physical function (RR 4.44, p = 0.01). Older age was not associated with either objective or PRO impairment. DISCUSSION: Cognitive impairment, using objective and PRO screening measures, was relatively common in adults with PCDs. Cancer-related factors and medical comorbidities were associated with objective cognitive impairment whereas psychosocial and functional factors were associated with PRO impairment.

Geriatric-assessment-identified functional deficits among adults with multiple myeloma with normal performance status.

OBJECTIVES: Findings from a brief geriatric assessment (GA) in a cohort of adults with multiple myeloma (MM) are presented, with particular attention to the utility of the GA in identifying important deficits in adults judged to have a normal Karnofsky Performance Status (KPS ≥ 80). MATERIALS AND METHODS: Adults age 18 and older with MM were recruited into an observational study from 2018 to 2020. A modified Cancer and Aging Research Group (CARG) GA was administered at enrollment. Enrollees also completed the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life of Cancer Patients Core 30 questionnaire (QLQ-C30), with subscales of physical, social, role, and cognitive functioning (range 0-100; higher values indicate better function). Data were analyzed using descriptive statistics for the full cohort and stratified by concurrent KPS (score < 80 vs ≥ 80). RESULTS: Among 89 adults, the mean age was 69.1 years, 68% were aged ≥65 years, and 70% were white. In this cohort, 78% had KPS ≥ 80. Among those with KPS ≥ 80, functional impairments (Timed Up and Go ≥14 s and dependence in ≥1 instrumental activity of daily living) were seen in 30% and 21%, respectively, with 11% reporting ≥1 fall in the prior 6 months. At least two GA-identified deficits were detected in 50% of the overall cohort and in 41% of those with KPS ≥ 80. Among those with KPS ≥ 80, self-reported physical impairment on EORTC QLQ-C30 was noted by 34%. CONCLUSION: Using a modified CARG GA and EORTC questionnaire, functional impairments were identified among adults considered to have a good performance status based on a KPS (≥ 80). Future studies should focus on using GA measures for therapy assignment and identifying opportunities for intervening upon GA-identified deficits.

Preclinical Evaluation of B7-H3-specific Chimeric Antigen Receptor T Cells for the Treatment of Acute Myeloid Leukemia.

PURPOSE: The development of safe and effective chimeric antigen receptor (CAR) T-cell therapy for acute myeloid leukemia (AML) has largely been limited by the concomitant expression of most AML-associated surface antigens on normal myeloid progenitors and by the potential prolonged disruption of normal hematopoiesis by the immunotargeting of these antigens. The purpose of this study was to evaluate B7-homolog 3 (B7-H3) as a potential target for AML-directed CAR T-cell therapy. B7-H3, a coreceptor belonging to the B7 family of immune checkpoint molecules, is overexpressed on the leukemic blasts of a significant subset of patients with AML and may overcome these limitations as a potential target antigen for AML-directed CAR-T therapy. EXPERIMENTAL DESIGN: B7-H3 expression was evaluated on AML cell lines, primary AML blasts, and normal bone marrow progenitor populations. The antileukemia efficacy of B7-H3-specific CAR-T cells (B7-H3.CAR-T) was evaluated using in vitro coculture models and xenograft models of disseminated AML, including patient-derived xenograft models. The potential hematopoietic toxicity of B7-H3.CAR-Ts was evaluated in vitro using colony formation assays and in vivo in a humanized mouse model. RESULTS: B7-H3 is expressed on monocytic AML cell lines and on primary AML blasts from patients with monocytic AML, but is not significantly expressed on normal bone marrow progenitor populations. B7-H3.CAR-Ts exhibit efficient antigen-dependent cytotoxicity in vitro and in xenograft models of AML, and are unlikely to cause unacceptable hematopoietic toxicity. CONCLUSIONS: B7-H3 is a promising target for AML-directed CAR-T therapy. B7-H3.CAR-Ts control AML and have a favorable safety profile in preclinical models.

Chimeric antigen receptor T-cells for B-cell malignancies.

The adoptive transfer of T-lymphocytes modified to express chimeric antigen receptors (CAR-Ts) has produced impressive clinical responses among patients with B-cell malignancies. This has led to a rapid expansion in the number of clinical trials over the past several years. Although CD19-specific CAR-Ts are the most extensively evaluated, CAR-Ts specific for other B-cell-associated targets have also shown promise. However, despite this success, toxicities associated with CAR-T administration remain a significant concern. There continues to be substantial heterogeneity among CAR-T products, and differences in both CAR designs and CAR-T production strategies can substantially affect clinical outcomes. Ongoing clinical studies will further elucidate these differences and many other innovative approaches are being evaluated at the preclinical level. In this review, we will discuss the background and rationale for the use of CAR-Ts, provide an overview of advances in the field, and examine the application of CAR-Ts to the treatment of B-cell malignancies, including a summary of clinical trials published to date.

Single agent lenalidomide three times a week induces hematologic responses in AL amyloidosis patients on dialysis.

The combination of lenalidomide and dexamethasone can produce hematologic responses in previously treated patients with AL amyloidosis. Because lenalidomide is primarily excreted unchanged by the kidney, adjustments to the starting dose of lenalidomide are recommended to provide appropriate drug exposure in patients with moderate or severe renal impairment and in patients on dialysis. Here, we report on a study of patients with AL amyloidosis on dialysis treated with lenalidomide at a dose of 10 mg orally three times a week. Seven patients were enrolled. All patients had received prior treatment, with 57% receiving prior high-dose melphalan and stem cell transplantation. Two patients died before evaluation of response. The most common adverse event was infection; no thromboembolic complications were seen. One patient required dose-modification. Hematologic responses were obtained by four of the five evaluable patients. Median overall survival was 18 months. In conclusion, adjusted dose lenalidomide was reasonably tolerated and induced sustained hematologic responses in previously treated patients with AL amyloidosis on dialysis.

Short-term weight loss attenuates local tissue inflammation and improves insulin sensitivity without affecting adipose inflammation in obese mice.

Obesity is a major cause of insulin resistance, and weight loss is shown to improve glucose homeostasis. But the underlying mechanism and the role of inflammation remain unclear. Male C57BL/6 mice were fed a high-fat diet (HFD) for 12 wk. After HFD, weight loss was induced by changing to a low-fat diet (LFD) or exercise with continuous HFD. The weight loss effects on energy balance and insulin sensitivity were determined using metabolic cages and hyperinsulinemic euglycemic clamps in awake mice. Diet and exercise intervention for 3 wk caused a modest weight loss and improved glucose homeostasis. Weight loss dramatically reduced local inflammation in skeletal muscle, liver, and heart but not in adipose tissue. Exercise-mediated weight loss increased muscle glucose metabolism without affecting Akt phosphorylation or lipid levels. LFD-mediated weight loss reduced lipid levels and improved insulin sensitivity selectively in liver. Both weight loss interventions improved cardiac glucose metabolism. These results demonstrate that a short-term weight loss with exercise or diet intervention attenuates obesity-induced local inflammation and selectively improves insulin sensitivity in skeletal muscle and liver. Our findings suggest that local factors, not adipose tissue inflammation, are involved in the beneficial effects of weight loss on glucose homeostasis.

Emerging therapies for systemic lupus erythematosus--focus on targeting interferon-alpha.

Current therapies for systemic lupus erythematosus (SLE), a debilitating, potentially lethal, multifactorial systemic autoimmune disease, are limited to suppressing disease activity and are associated with multiple adverse effects. Recent advances in basic and translational sciences have elucidated a crucial role for the interferon-alpha (IFNα) pathway in the pathogenesis of this enigmatic disease. The so-called "type I interferon signature" has emerged as a major risk factor for disease activity of SLE. Multiple genes encoding for molecules within the type I interferon pathway have been associated with SLE in genome wide association studies. In addition, innate immune receptors are thought to be triggered by either endogenous and/or exogenous stimuli that lead to hypersecretion of IFNα. We review the multiple emerging treatment strategies targeting IFNα-related pathways. These include monoclonal antibodies against IFNα, anti-IFNα antibody-inducing vaccines, and inhibitors of Toll-like receptors. We also summarize the current status of these pharmaceutical agents in early clinical trials.

Primary atmospheric oxidation mechanism for toluene.

The products of the primary OH-initiated oxidation of toluene were investigated using the turbulent flow chemical ionization mass spectrometry technique at temperatures ranging from 228 to 298 K. A major dienedial-producing pathway was detected for the first time for toluene oxidation, and glyoxal and methylglyoxal were found to be minor primary oxidation products. The results suggest that secondary oxidation processes involving dienedial and epoxide primary products are likely responsible for previous observations of glyoxal and methylglyoxal products from toluene oxidation. Because the dienedial-producing pathway is a null cycle for tropospheric ozone production and glyoxal and methylglyoxal are important secondary organic aerosol precursors, these new findings have important implications for the modeling of toluene oxidation in the atmosphere.